Apafant is a compound represented by a chemical name of 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thien o[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine (see the following structural formula [I]) and is known to exhibit a high antagonistic activity on a triazolodiazepine platelet activating factor (hereinafter referred to as PAF) (Japanese Laid-open Patent Publication No. 176591/1986). ##STR1##
PAF is an inflammatory chemical mediator which has a very high physiological activity and is proved to participate in diseases such as inflammatory diseases (e.g. asthma, nephritis), disseminated intravascular coagulation syndrome and shock.
Various medicinal uses are already known regarding apafant, which has strong antagonism to PAF. For example, WO93/07129 discloses that apafant is useful as a therapeutic agent for osteoporosis because it has an inhibitory effect on absorption of bones. Japanese Laid-open Patent Publication No. 106826/1991 discloses that apafant is useful for cardiopathy such as heart failure because it was recognized to inhibit .beta.-adrenoreceptor-mediated contraction decrease in hearts of rats whose spinae had been broken. WO90/01927 discloses that apafant is useful for autoimmune diseases because it was recognized to increase platelets in patients with idiopathic thrombocytopenic purpura. It was also reported that apafant increased survival rates concentration-dependently against anaphylactic shock (J. Pharmacol. Exp. Ther., 260, 748-755 (1992)) and exhibited antagonism to hypotension induced by endotoxin or PAF (Eur. J. Pharmacol., 135, 117-122 (1987)). In addition, it was reported that apafant completely prevented any increase in airway resistance after PAF inhalation and inhibited development of cardiovascular and side effects induced by PAF in double-blind clinical pharmacological tests (Clin. Pharmacol. Ther., 47, 456-462 (1990)).
As ophthalmic application, WO91/18608 discloses that apafant can also be used in eyes etc. topically as an antipruritic because it inhibits an itching-inducing activity of PAF. However, it does not disclose an aqueous ophthalmic solution containing apafant as an active ingredient.
Thus, stability of apafant in an aqueous ophthalmic solution is discussed in order to develop the aqueous ophthalmic solution containing apafant, which is useful as a medicine, i.e., as an active ingredient. However, there exists the problem that a stable aqueous ophthalmic solution of apafant cannot be obtained if the formulation of apafant is attempted using conventional techniques. Accordingly, it is necessary to solve the instability problem of apafant in the aqueous ophthalmic solution in order to develop the aqueous ophthalmic solution containing apafant as the active ingredient.